T lymphocytes must respond to specific antigen by rapid proliferation and differentiation to mount an effective immune response. It is critical that this occur only in response to foreign antigen, so that self antigens do not induce autoimmune responses. Tolerance to self-antigen is achieved in part by negative selection in the thymus. This is not complete, however, and some self-reactive T cells escape into the periphery. Mechanisms exist for rendering these mature T cells tolerant, but they are poorly understood. This Program is addressing the nature of these mechanisms in mature T cells using both in vitro and in vivo models. Peripheral tolerance in CD4 T cells is being studied in Projects I (Jenkins) and II (Mueller), and in CDS T cells in Projects III (Hogquist) and IV (Mescher). Thus, both major subsets of T cells are being studied. In addition, Projects I and III examine CD4 and CDS T cell tolerance at the biological level using novel models, and Projects II and IV examine tolerance mechanisms in CD4 and CDS T cells at the molecular levels. The planned work involves extensive collaborative interactions among the investigators. It is anticipated that the findings obtained in these studies will contribute to a better understanding of how autoimmunity is avoided. Understanding of these mechanisms, and hence how to manipulate them, has the potential to contribute to improvements in transplantation and disease therapy. Mechanisms that induce tolerance to self-antigens may also induce tolerance to foreign antigens, including those present on tumors or virus-infected cells, resulting in the immune system failing to mount a protective response. Finally, there is great potential for using defined peptide antigens to induce protective or therapeutic immunity for a broad range of diseases and a great deal of current effort is focusing on this. However, it is becoming increasingly clear that these must be used with great caution since they can also induce tolerance that may lead to lessened protection or exacerbated disease. Thus, developing a better understanding of the mechanisms that can lead to T cell tolerance, as proposed in this Program, has implications well beyond autoimmune diseases.